Dysregulation of lncRNA-CCRR contributes to brain metastasis of breast cancer by intercellular coupling via regulating connexin 43 expression

Cardiac conduction regulatory RNA (CCRR) is down-regulated in the pathogenesis of heart failure (HF), which accordingly suppresses cardiac conduction while promoting arrhythmogenicity. Meanwhile, CX43 was reported to play a role in the pathogenesis of metastatic breast cancer and melanoma brain colonization. In this study, we studied the role of long non-coding RNA CCRR and its interaction with CX43 in brain metastasis of breast cancer. Breast cancer patients were grouped according to the metastasis status. Real-time PCR and IHC assay were used to measure the expression of lncRNA-CCRR and CX43 in patients. Western blot was conducted to observe the effect of lncRNA-CCRR on the expression of CX43 in MDA-MB-231BR and BT-474BR cells. Compared with the non-metastasis group, the mRNA expression of tissue lncRNA-CCRR, cerebrospinal fluid (CSF) lncRNA-CCRR, tissue CX43 and tissue protein expression of CX43 were both evidently up-regulated in metastasis patients, especially in patients with brain metastasis. The expression of lncRNA-CCRR was positively correlated with the up-regulated expression of CX43. Moreover, CX43 expression was significantly lower in MDA-MB-231WT cells compared with that in MDA-MB-231BR cells. Also, the overexpression of lncRNA-CCRR evidently increased dye transfer rate from astrocytes to MDA-MB-231BR/BT-474BR cells but reduced lncRNA-CCRR expression and suppressed the transmigration of MDA-MB-231BR/BT-474BR cells in a blood-brain barrier (BBB) model. In this study, we demonstrated that the presence of lncRNA-CCRR could up-regulate the expression of CX43, which promoted gap junction formation in brain metastasis of breast cancer. Accordingly, the communication between breast cancer cells and astrocytes was also promoted.